Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2ccnc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1(N)CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The procedure described in Example 2 is followed up to the end of step (c). A solution of 6.81 g (0.021 mol) of 4-t-butoxycarbonylamino-1-(2-chloropyrimidin-4-yl)-4-methylpiperidine (step c) in 80 ml of anhydrous methylene chloride is cooled under a nitrogen atmosphere and 16.4 ml of anisole and 83 ml of trifluoroacetic acid are added slowly. The mixture is stirred for 1 hour at room temperature and 80 ml of a 30% solution of NaOH are added slowly. The reaction medium is extracted with methylene chloride and dried over Na2SO4 and the solvent and the anisole are evaporated off under reduced pressure to give 4-amino-1-(2-chloropyrimidin-4-yl)-4-methylpiperidine as the base, which is treated with maleic acid in an ethanol/ethyl ether mixture. The maleate obtained in this way is isolated by filtration (yield 65%, m.p. 125°-126° C.).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:24]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol) in DMSO (2 mL) was added diethylamine (173 mg, 2.37 mmol) and DIEA (170 mg, 1.32 mmol). The resulting solution was stirred overnight at 70° C. and then quenched by the addition of water/ice (40 mL), extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via silica gel column chromatography (0.5%-4% ethyl acetate in petroleum ether) afforded methyl 3-(diethylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (100 mg, 60%).
Reaction SMILES: [CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3C1.[CH2:13]1C2=C3C(=CC=C2)C=CC=C3C1.CC12CC3CC(CC(C)(C3)C1)C2>>[CH2:4]([C:5]12[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:1]1)[CH2:13]2)[CH3:3]
Reactant: c1cc2c3c(cccc3c1)CC2
Reactant: C1CC2CCCC3CCC(C1)C23
Agent: CC12CC3CC(C1)CC(C)(C3)C2
Product: CCC12CC3CC(CC(C3)C1)C2

Procedure:
The same experiment as described in 2th line from the bottom in Table 5 of Example 5 was carried out except that perhydroacenaphthene prepared by hydrogenation of acenaphthene was used in place of TMN. Conversion rate of perhydroacenaphthene was 75.4%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 33.0% and 47.1% of selectivity and at 24.9% and 35.0% of yield respectively. Moreover, when amounts of catalyst was increased from 2 g to 4 g, conversion rate of perhydroacenaphthene was 85.6%, and 1,3-dimethyladamantane and 1-ethyladamantane were obtained at 45.2% and 6.6% of selectivity and at 38.7% and 5.7% of yield respectively.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]([Si:33]([CH3:43])([CH3:42])[O:34][CH2:35][C:36]([CH3:41])([CH:38]1[CH2:40][O:39]1)[CH3:37])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Si:33]([O:34][CH2:35][C:36]([CH3:37])([CH3:41])[CH:38]([OH:39])[CH2:40][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:43])[CH3:42]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2.0 g), tert-butyl(dimethyl) (2-methyl-2-oxirane-2-ylpropoxy)silane (3.75 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (15 mL) was stirred at 80° C. for 24 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.36 g, 43%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:22])[N:9]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](N(CC)CC)[CH3:24].CN(C)[CH:32]=[O:33]>>[O:13]=[C:10]1[N:9]([C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[C:8](=[O:22])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12][N:11]1[CH2:23][CH2:24][CH:32]=[O:33]
Reactant: O=C(c1ccccc1)n1c(=O)[nH]nc(-c2ccccc2)c1=O
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Product: O=CCCn1nc(-c2ccccc2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a solution of 6-phenyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (84 mg, 0.286 mmol) in N,N-Dimethylformamide (DMF) (2 ml) under an argon atmosphere, triethylamine (0.050 ml, 0.359 mmol) was added and the mixture stirred at r.t. for 5 min., then acroleyn (0.020 ml, 0.299 mmol) was added and the mixture stirred overnight. Reaction was quenched by sat. NH4Cl (4 mL) and aq. layer extracted by Et2O (2×10 mL). Combined organic layers were washed by iced water, dried upon sodium sulphate and concentrated under reduced pressure to obtain 77 mg of title (77% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]OS(OC)(=O)=O.Cl>[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:24])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
N-Benzyloxycarbonyl-L-tyrosine (31.5 g, 0.1 mol) was dissolved in aqueous sodium hydroxide (10 g in 100 ml H2O) and dimethylsulphate (10.5 ml, 0.11 mol) added dropwise to the stirred solution. The reaction was stirred overnight, additional dimethylsulphate (2 ml) added in one portion and the reaction stirred for a further 48 hours. 2M Hydrochloric acid was added until a white precipitate formed. This was filtered off, taken up in ethyl acetate, washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated. The residue was crystallised from ethyl acetate to give N-benzyloxycarbonyl-O-methyl-L-tyrosine (5.8 g, 18%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51]CC5C=CC(Cl)=C(Cl)C=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.CCN(CC)CC>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)CO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (1.0 g) was dissolved in EtOAc (4.0 mL), MeOH (12.0 mL), NEt3 (0.236 g), followed by catalytic amount of 10% palladium on activated carbon (wet) was added. After degassing, hydrogen was introduced through a balloon; the reaction mixture was stirred at room temperature for 1.0 hour. The reaction mixture was then filtered through celite, the celite cake was washed three times with ethyl acetate, and the filtrates combined. The solvent was then removed in vacuo, dried under vacuum to get 0.81 g of title compound. LCMS (m/z): 695.
Reaction SMILES: Br[CH2:2][C@H:3]([O:16][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(OCC)C>O1CCOCC1>[CH2:24]([NH:31][CH2:2][C@@H:3]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=1)[O:16][Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CC[Si](CC)(CC)O[C@@H](CNCc1ccccc1)c1ccc2c(c1)COC(C)(C)O2
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of {[(1R)-2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane (130 g) and benzylamine (177 ml) in 1,4-dioxane (650 ml) was heated at 105° C. with stirring overnight. The mixture was then cooled to room temperature and water (150 ml) and diethyl ether (1200 ml) added. The layers were separated and the ethereal layer was washed with saturated ammonium chloride solution (3×600 ml), saturated sodium bicarbonate solution (200 ml) and then brine (200 ml). The solution was dried over anhydrous Na2SO4 before being filtered and concentrated under reduced pressure to give the title compound (129.9 g) as an oil, δ (CDCl3) 7.22 (5H, m), 7.02 (1H, d, J 8.7 Hz), 6.86 (1H, s), 6.68 (1H, d, J 8.3 Hz), 4.75 (2H, s), 4.69 (1H, m), 3.73 (2H, s), 2.70 (2H, m), 1.46 (6H, s), 0.79 (9H, m), 0.44 (6H, m).
Reaction SMILES: [C:1]1([C:17]2C=C[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH:16]2[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]2)[CH2:10]1)=[O:8].C(OC(N1CCC2C(NC2)C1)=O)(C)(C)C.[S:38]1C=CC=C1C1C=CC=CC=1C(Cl)=O.C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[C@@H:16]12[N:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:17]3[S:38][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:10][C@@H:11]1[CH2:12][CH2:13][NH:14][CH2:15]2
Reactant: O=C(Cl)c1ccccc1-c1cccs1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Agent: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: O=C(c1ccccc1-c1cccs1)N1C[C@@H]2CCNC[C@@H]21
Yield: 66.7 %

Procedure:
Intermediate 7 was prepared in a manner analogous to Intermediate 3, substituting (1R,6S) 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 2-thiophen-2-yl-benzoyl chloride for biphenyl-2-carbonyl chloride in Step A. The final compound was concentrated and the residue was purified on HPLC to provide the title compound (150 mg, 66.7%). MS (ESI) mass calcd. for C17H18N2OS, 298.4; m/z found, 299.2. [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3](Cl)[CH2:4][Cl:5].C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=[C:33]3[C:26](N=[C:28]([NH:30][C:31]3=O)[NH2:29])=[N:25][CH:24]=2)=CC=1)=O)C(O)=O.[CH3:39]S(C)=O>Cl>[ClH:5].[CH3:39][N:25]([CH3:24])[CH2:26][CH2:33][CH2:31][N:30]=[C:28]=[N:29][CH2:3][CH3:4]
Reactant: ClCCCl
Reactant: CS(C)=O
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C

Procedure:
A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC*HCl) and FA in anhydrous DMSO was prepared and stirred at room temperature until FA was well dissolved (1 h). Chitosan was dissolved in 0.1 M hydrochloric acid, to produce a solution with a concentration of 1 mg/ml, and then adjusted to pH 5.5 with 0.10 M sodium hydroxide solution. After the dropwise addition of EDC*HCl (m=5.1 mg in 1 ml distilled water) to the chitosan solution (V=20 ml), the reaction mixture was stirred for 10 min. Then folic acid (m=8.5 mg in dimethyl sulfoxide, V=1 ml) was added to the reaction mixture. The resulting mixture was stirred at room temperature in the dark for 24 h. It was brought to pH 9.0 by drop wise addition of diluted aqueous NaOH and was washed three times with aqueous NaOH, and once with distilled water. The polymer was isolated by lyophilization.
Reaction SMILES: [C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]2[C:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][C:27]=2[F:39])=[N:17]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][N:11]3[C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of 2-cyano-4-methyl-pent-2-enoic acid (30.7 mg, 0.220 mmol), 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL, 0.440 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded 30 mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (30 mg, 0.0586 mmol, 39.8% yield) as judged by LCMS. (M+1=512).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][C:12]4([CH2:17][CH2:16]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][C:12]4([CH2:16][CH2:17]4)[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)CC12CC2
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CC12CC2

Procedure:
The title compound is prepared from a mixture of 8′-chloro-2′-methyl-1′,2′,4′,5′-tetrahydrospiro[cyclopropane-1,3′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:28][C:29]1[NH:33][C:32]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:31]=2[N:30]=1.C(N(CC)C(C)C)(C)C.[I-].[K+]>C(#N)C>[N:1]1[C:10]2[CH:9]([N:11]([CH2:28][C:29]3[NH:30][C:31]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:32]=4[N:33]=3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: FC(F)(F)c1ccc2nc(CCl)[nH]c2c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C1CCCc2cccnc21
Yield: 75.4 %

Procedure:
2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (160 mg, 0.46 mmol) and 2-chloromethyl-6-trifluoromethyl-1H-benzoimidazole (129 mg, 0.55 mmol), N,N-diisopropylethylamine (100 μL, 0.60 mmol), and potassium iodide (8 mg, 0.05 mmol) in acetonitrile were stirred at 40° C. for 3 days. Then the reaction mixture was cooled and the solvent was removed under reduced pressure to afford a red oil. Purification by flash column chromatography on silica gel using NH4OH/CH3OH/CH2Cl2 (1:2:97) afforded the product as an orange foam (190 mg, 76%). 1H NMR (CDCl3) δ 1.37-1.45 (m, 5H), 1.56-1.70 (m, 2H), 2.18-2.20 (m, 1H), 2.57-2.61 (m, 1H), 2.72-2.80 (m, 3H), 3.49-3.54 (m, 2H), 3.98-4.16 (m, 3H), 7.13-7.15 (m, 1H), 7.40-7.45 (m, 2H), 7.62-7.74 (m, 5H), 7.86 (br m, 1H), 8.62 (br m, 1H).
Reaction SMILES: C1(CO[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)CCC1.[O:19]=[C:20]1[C:25]2[C:26]([CH2:29][OH:30])=[CH:27][O:28][C:24]=2[CH2:23][CH2:22][CH2:21]1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:19]=[C:20]1[C:25]2[C:26]([CH2:29][O:30][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:8]=3[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]4)=[CH:27][O:28][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: O=C1CCCc2occ(CO)c21
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: O=C(O)c1cc2c(OCc3coc4c3C(=O)CCC4)cccc2[nH]1

Procedure:
4-(4-Oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (16f) is synthesized analogous to 16a from 4-oxo-4,5,6,7-tetrahydro-benzofuran-3-ylmethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cccc(F)c1
Product: CN1CCCn2c1cc(OCc1cccc(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.N1CCCCC1>C(O)C>[Br-:1].[CH2:2]([N+:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:35]/[C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH3:15])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC[n+]1ccc(C)c2ccccc21
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCO
Product: CC[n+]1ccc(/C=C/c2ccc3c(c2)c2ccccc2n3CCOCCOC)c2ccccc21
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution mixture of 6 (0.20 g, 0.8 mmol), 3a (0.33 g, 1.1 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLE (0.22 g) in 53% yield.1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J=8.4 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.54-8.51 (m, 2H), 8.44 (d, J=16 Hz, 1H), 8.36 (d, J=16 Hz, 1H), 8.28-8.23 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 4.99 (tr, J=6.8 Hz, 2H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 1.59 (t, J=6.8 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.2, 146.7, 145.1, 142.2, 140.9, 137.7, 135.0, 128.9, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.2, 115.5, 110.4, 110.3, 71.3, 69.8, 68.9, 58.1, 51.9, 15.1. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O2 451.2380 Found 451.2362 [M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN1C(=O)CCC1.O>C(OCC)C>[CH:9]1([O:8][C:5]2[CH:4]=[CH:3][C:2]([C:17]#[N:18])=[N:7][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#C[Cu]
Reactant: Clc1ccc(OC2CCCCCC2)cn1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(OC2CCCCCC2)cn1
Temperature: 190 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
Add 6-chloro-3-cycloheptyloxy-pyridine (2.35 g, 10.4 mmol) and copper(I) cyanide (1.16 g, 13.1 mmol) to NMP (25 mL). Heat the mixture to 190° C. and stir overnight. Cool the mixture to room temperature, add water (50 mL) and diethyl ether (30 mL). Extract the aqueous phase with diethyl ether (3×25 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (1.21 g, 54%). MS (APCI+) m/z: 217 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:14]([CH2:17][C:18]([O:20][CH2:21]C)=[O:19])=[N+:15]=[N-:16].C[O-].[Na+]>CO.[Cl-].[Na+].O>[N:14]([C:17](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(-n2ccnc2)cc1)N=[N+]=[N-]
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-(1-imidazolyl)benzaldehyde (1.41 g, 8.16 mol) and ethyl azidoacetate (10.6 g, 81.7 mmol) in MeOH (50 ml) under nitrogen atmosphere is added sodium methoxide (28 wt. % solution in MeOH, 13,2 ml, 65 mmol) dropwise. Stirring is continued for 1.5 h. Then, the reaction mixture is diluted with brine (100 ml) and extracted with three portions of ether. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give methyl 2-azido-3-[4-(1-imidazolyl)phenyl]-2-propenate.